The scientific emphasis of this proposal is to determine the role that pancreatic cancer associated fibroblasts (CAFs) play in tumor evolution using novel mouse modeling and functional in vitro assays. The pancreatic tumor microenvironment - which makes up over half of the tumor volume - is known to play an important role in tumor development and drug resistance. The hedgehog paracrine loop between epithelial and stromal cells has been widely discussed in the literature and its mis-regualtion in cancer has recently become evident. Briefly, tumor cells secrete hedgehog ligands that activate surrounding stromal fibroblasts, thus leading to their secretion of pro-tumor factors In this project, we aim to study the effect of disrupting this feedback loop by deleting a key hedgehog ligand receptor in stromal fibroblasts. Specifically, using novel mouse models developed in our lab, we show that conditionally deleting the hedgehog ligand receptor smoothened (Smo) exclusively in the fibroblast compartment leads to accelerated Kras-driven tumorigenesis. Thus, we have discovered a novel tumor suppressive role for SMO in pancreatic fibroblasts and this project will further characterize the pro-tumor mechanisms upon deletion of Smo in pancreatic CAFs. Additionally, this result provides some rationale for the recent failure of SMO inhibitor clinical trials in pancreatic cancer patients. Furthering the understanding of pro-tumor mechanisms in Smonull fibroblasts will provide key insight into why these trials have failed and potentially offer new therapeutic avenues. Through experiments described in this proposal, we will study alterations in tumor development over time and characterize the effects of deleting Smo in pancreatic fibroblasts using in vivo mouse modeling.